tbuckley/cabot-search huggingface dataset:
Self-adaptive nanoassembly enabling turn-on hypoxia illumination and periphery/center closed-loop tumor eradication
Authors: Ziyue Wang, Shenwu Zhang, Zhiqiang Kong, Songhao Li, Jin Sun, Ying Zheng, Zhonggui He, Hao Ye, Cong Luo
Journal: Cell Reports Medicine (2023)

Solid tumors are regarded as complex evolving systems rather than simple diseases. Self-adaptive synthetic therapeutics are required to cope with the challenges of entire tumors; however, limitations in accurate positioning and destruction of hypoxic niches seriously hinder complete tumor eradication. In this study, we engineer a molecular nanoassembly of sorafenib and a hypoxia-sensitive cyanine probe (CNO) to facilitate periphery/center synergistic cancer therapies. The self-adaptive nanoassembly with cascade drug release features not only effectively kills the peripheral tumor cells in normoxic rims but precisely illuminates hypoxic niches following the reduction of CNO by nitroreductase. More important, CNO is found to synergistically induce tumor ferroptosis with sorafenib via nicotinamide adenine dinucleotide phosphate (NADPH) depletion in hypoxic niches. As expected, the engineered nanoassembly demonstrates self-adaptive hypoxic illumination and periphery/center synergetic tumor eradication in colon and breast cancer BALB/c mouse xenograft models. This study advances turn-on hypoxia illumination and chemo-ferroptosis toward clinical applicability.
CRISPR-based functional genomics screening in human-pluripotent-stem-cell-derived cell types
Authors: Kun Li, Miao Ouyang, Jiangshan Zhan, Ruilin Tian
Journal: Cell Genomics (2023)

While our knowledge of gene expression in different human cell types is rapidly expanding with advances in transcriptomic profiling technologies, the next challenge is to understand gene function in each cell type. CRISPR-Cas9-based functional genomics screening offers a powerful approach to determine gene function in a high-throughput manner. With the maturation of stem cell technology, a variety of human cell types can be derived from human pluripotent stem cells (hPSCs). Recently, the integration of CRISPR screening with hPSC differentiation technologies opens up unprecedented opportunities to systematically examine gene function in different human cell types and identify mechanisms and therapeutic targets for human diseases. This review highlights recent progress in the development and applications of CRISPR-Cas9-based functional genomics screening in hPSC-derived cell types, discusses current challenges and limitations, and outlines future directions for this emerging field.
A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration
Authors: Luz D. Orozco, Leah A. Owen, Jeffrey Hofmann, Amy D. Stockwell, Jianhua Tao, Susan Haller, Vineeth T. Mukundan, Christine Clarke, Jessica Lund, Akshayalakshmi Sridhar, Oleg Mayba, Julie L. Barr, Rylee A. Zavala, Elijah C. Graves, Charles Zhang, Nadine Husami, Robert Finley, Elizabeth Au, John H. Lillvis, Michael H. Farkas, Akbar Shakoor, Richard Sherva, Ivana K. Kim, Joshua S. Kaminker, Michael J. Townsend, Lindsay A. Farrer, Brian L. Yaspan, Hsu-Hsin Chen, Margaret M. DeAngelis
Journal: Cell Genomics (2023)

Age-related macular degeneration (AMD) is a leading cause of blindness, affecting 200 million people worldwide. To identify genes that could be targeted for treatment, we created a molecular atlas at different stages of AMD. Our resource is comprised of RNA sequencing (RNA-seq) and DNA methylation microarrays from bulk macular retinal pigment epithelium (RPE)/choroid of clinically phenotyped normal and AMD donor eyes (n = 85), single-nucleus RNA-seq (164,399 cells), and single-nucleus assay for transposase-accessible chromatin (ATAC)-seq (125,822 cells) from the retina, RPE, and choroid of 6 AMD and 7 control donors. We identified 23 genome-wide significant loci differentially methylated in AMD, over 1,000 differentially expressed genes across different disease stages, and an AMD Müller state distinct from normal or gliosis. Chromatin accessibility peaks in genome-wide association study (GWAS) loci revealed putative causal genes for AMD, including
Identification of genetic variants that impact gene co-expression relationships using large-scale single-cell data
Authors: Shuang Li, Katharina T. Schmid, Dylan H. de Vries, Maryna Korshevniuk, Corinna Losert, Roy Oelen, Irene V. van Blokland, Hilde E. Groot, Morris A. Swertz, Pim van der Harst, Harm-Jan Westra, Monique G.P. van der Wijst, Matthias Heinig, Lude Franke
Journal: Genome biology (2023)

Expression quantitative trait loci (eQTL) studies show how genetic variants affect downstream gene expression. Single-cell data allows reconstruction of personalized co-expression networks and therefore the identification of SNPs altering co-expression patterns (co-expression QTLs, co-eQTLs) and the affected upstream regulatory processes using a limited number of individuals.
The ENCODE Imputation Challenge: a critical assessment of methods for cross-cell type imputation of epigenomic profiles
Authors: Jacob Schreiber, Carles Boix, Jin wook Lee, Hongyang Li, Yuanfang Guan, Chun-Chieh Chang, Jen-Chien Chang, Alex Hawkins-Hooker, Bernhard Schölkopf, Gabriele Schweikert, Mateo Rojas Carulla, Arif Canakoglu, Francesco Guzzo, Luca Nanni, Marco Masseroli, Mark James Carman, Pietro Pinoli, Chenyang Hong, Kevin Y. Yip, Jeffrey P. Spence, Sanjit Singh Batra, Yun S. Song, Shaun Mahony, Zheng Zhang, Wuwei Tan, Yang Shen, Yuanfei Sun, Minyi Shi, Jessika Adrian, Richard Sandstrom, Nina Farrell, Jessica Halow, Kristen Lee, Lixia Jiang, Xinqiong Yang, Charles Epstein, J. Seth Strattan, Bradley Bernstein, Michael Snyder, Manolis Kellis, William Stafford, Anshul Kundaje
Journal: Genome biology (2023)

A promising alternative to comprehensively performing genomics experiments is to, instead, perform a subset of experiments and use computational methods to impute the remainder. However, identifying the best imputation methods and what measures meaningfully evaluate performance are open questions. We address these questions by comprehensively analyzing 23 methods from the ENCODE Imputation Challenge. We find that imputation evaluations are challenging and confounded by distributional shifts from differences in data collection and processing over time, the amount of available data, and redundancy among performance measures. Our analyses suggest simple steps for overcoming these issues and promising directions for more robust research.
SARS-CoV-2 spike host cell surface exposure promoted by a COPI sorting inhibitor
Authors: Yiqun Li, Mingrui Yang, Yanan Nan, Jiaming Wang, Sanjiao Wang, Dongxiao Cui, Jiajian Guo, Pengfei He, Wenxin Dai, Shuqi Zhou, Yue Zhang, Wenfu Ma
Journal: Acta Pharmaceutica Sinica B (2023)

Via an insufficient coat protein complex I (COPI) retrieval signal, the majority of SARS-CoV-2 spike (S) is resident in host early secretory organelles and a tiny amount is leaked out in cell surface. Only surface-exposed S can be recognized by B cell receptor (BCR) or anti-S therapeutic monoclonal antibodies (mAbs) that is the trigger step for B cell activation after S mRNA vaccination or infected cell clearance by S mAbs. Now, a drug strategy to promote S host surface exposure is absent. Here, we first combined structural and biochemical analysis to characterize S COPI sorting signals. A potent S COPI sorting inhibitor was then invented, evidently capable of promoting S surface exposure and facilitating infected cell clearance by S antibody-dependent cellular cytotoxicity (ADCC). Importantly, with the inhibitor as a probe, we revealed Omicron BA.1 S is less cell surface exposed than prototypes because of a constellation of S folding mutations, possibly corresponding to its ER chaperone association. Our findings not only suggest COPI is a druggable target against COVID-19, but also highlight SARS-CoV-2 evolution mechanism driven by S folding and trafficking mutations.
Orange-derived extracellular vesicles nanodrugs for efficient treatment of ovarian cancer assisted by transcytosis effect
Authors: Feng Long, Yao Pan, Jinheng Li, Suinan Sha, Xiubo Shi, Haoyan Guo, Chuanqing Huang, Qian Xiao, Chao Fan, Xingmei Zhang, Jun-Bing Fan, Ying Wang
Journal: Acta Pharmaceutica Sinica B (2023)

Extracellular vesicles (EVs) have recently received much attention about the application of drug carriers due to their desirable properties such as nano-size, biocompatibility, and high stability. Herein, we demonstrate orange-derived extracellular vesicles (OEV) nanodrugs (DN@OEV) by modifying cRGD-targeted doxorubicin (DOX) nanoparticles (DN) onto the surface of OEV, enabling significantly enhancing tumor accumulation and penetration, thereby efficiently inhibiting the growth of ovarian cancer. The obtained DN@OEV enabled to inducement of greater transcytosis capability in ovarian cancer cells, which presented the average above 10-fold transcytosis effect compared with individual DN. It was found that DN@OEV could trigger receptor-mediated endocytosis to promote early endosome/recycling endosomes pathway for exocytosis and simultaneously reduce degradation in the early endosomes-late endosomes-lysosome pathway, thereby inducing the enhanced transcytosis. In particular, the zombie mouse model bearing orthotopic ovarian cancer further validated DN@OEV presented high accumulation and penetration in tumor tissue by the transcytosis process. Our study indicated the strategy in enhancing transcytosis has significant implications for improving the therapeutic efficacy of the drug delivery system.
Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers
Authors: Bo Li, Hui Chen, Shaohua Yang, Feng Chen, Liangliang Xu, Yan Li, Mingzhe Li, Chengming Zhu, Fangyuan Shao, Xinhua Zhang, Chuxia Deng, Leli Zeng, Yulong He, Changhua Zhang
Journal: Molecular Cancer (2023)

Mesenchymal gastrointestinal cancers are represented by the gastrointestinal stromal tumors (GISTs) which occur throughout the whole gastrointestinal tract, and affect human health and economy globally. Curative surgical resections and tyrosine kinase inhibitors (TKIs) are the main managements for localized GISTs and recurrent/metastatic GISTs, respectively. Despite multi-lines of TKIs treatments prolonged the survival time of recurrent/metastatic GISTs by delaying the relapse and metastasis of the tumor, drug resistance developed quickly and inevitably, and became the huge obstacle for stopping disease progression. Immunotherapy, which is typically represented by immune checkpoint inhibitors (ICIs), has achieved great success in several solid tumors by reactivating the host immune system, and been proposed as an alternative choice for GIST treatment. Substantial efforts have been devoted to the research of immunology and immunotherapy for GIST, and great achievements have been made. Generally, the intratumoral immune cell level and the immune-related gene expressions are influenced by metastasis status, anatomical locations, driver gene mutations of the tumor, and modulated by imatinib therapy. Systemic inflammatory biomarkers are regarded as prognostic indicators of GIST and closely associated with its clinicopathological features. The efficacy of immunotherapy strategies for GIST has been widely explored in pre-clinical cell and mouse models and clinical experiments in human, and some patients did benefit from ICIs. This review comprehensively summarizes the up-to-date advancements of immunology, immunotherapy and research models for GIST, and provides new insights and perspectives for future studies.
Denosumab and incidence of type 2 diabetes among adults with osteoporosis: population based cohort study
Authors: Houchen Lyu, Sizheng Steven Zhao, Licheng Zhang, Jie Wei, Xiaoxiao Li, Hui Li, Yi Liu, Pengbin Yin, Vibeke Norvang, Kazuki Yoshida, Sara K Tedeschi, Chao Zeng, Guanghua Lei, Peifu Tang, Daniel H Solomon
Journal: BMJ (2023)

Abstract Objective To estimate the effect of denosumab compared with oral bisphosphonates on reducing the risk of type 2 diabetes in adults with osteoporosis. Design Population based study involving emulation of a randomized target trial using electronic health records. Setting IQVIA Medical Research Data primary care database in the United Kingdom, 1995-2021. Participants Adults aged 45 years or older who used denosumab or an oral bisphosphonate for osteoporosis. Main outcome measures The primary outcome was incident type 2 diabetes, as defined by diagnostic codes. Cox proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals, comparing denosumab with oral bisphosphonates using an as treated approach. Results 4301 new users of denosumab were matched on propensity score to 21 038 users of an oral bisphosphonate and followed for a mean of 2.2 years. The incidence rate of type 2 diabetes in denosumab users was 5.7 (95% confidence interval 4.3 to 7.3) per 1000 person years and in oral bisphosphonate users was 8.3 (7.4 to 9.2) per 1000 person years. Initiation of denosumab was associated with a reduced risk of type 2 diabetes (hazard ratio 0.68, 95% confidence interval 0.52 to 0.89). Participants with prediabetes appeared to benefit more from denosumab compared with an oral bisphosphonate (hazard ratio 0.54, 0.35 to 0.82), as did those with a body mass index ≥30 (0.65, 0.40 to 1.06). Conclusions In this population based study, denosumab use was associated with a lower risk of incident type 2 diabetes compared with oral bisphosphonate use in adults with osteoporosis. This study provides evidence at a population level that denosumab may have added benefits for glucose metabolism compared with oral bisphosphonates.
Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study
Authors: Bernard Zinman, Stewart B Harris, Jan Neuman, Hertzel C Gerstein, Ravi R Retnakaran, Janet Raboud, Ying Qi, Anthony JG Hanley
Journal: The Lancet (2010)
Efficacy of Chest Physiotherapy and Intermittent Positive-Pressure Breathing in the Resolution of Pneumonia
Authors: William G. B. Graham, Deborah A. Bradley, Rhonda Kleczek, Diantha Bartlett
Journal: New England Journal of Medicine (1978)

We undertook a randomized clinical trial to evaluate the efficacy of chest physiotherapy and intermittent positive-pressure breathing in the treatment of pneumonia. The diagnosis of pneumonia required a compatible clinical history and x-ray confirmation. A total of 54 patients were assigned to treatment and control groups and were similar in age, smoking history, underlying lung disease and prior antibiotic treatment. Antibiotic therapy, guided by Gram stain and sputum and blood cultures, was similar in both groups. Chest physiotherapy, consisting of postural drainage, percussion and vibration, was given concurrently with intermittent positive-pressure breathing with use of racemic epinephrine every four hours. There was no statistically significant difference in duration of fever, extent of radiographic clearing, duration of hospital stay and mortality between the control and treated groups. Chest physiotherapy and intermittent positive-pressure breathing do not hasten the resolution of pneumonia. (N Engl J Med 299:624–627, 1978)
Intratumor childhood vaccine-specific CD4<sup>+</sup>T-cell recall coordinates antitumor CD8<sup>+</sup>T cells and eosinophils
Authors: Michael C Brown, Georgia M Beasley, Zachary P McKay, Yuanfan Yang, Annick Desjardins, Dina M Randazzo, Daniel Landi, David M Ashley, Darell D Bigner, Smita K Nair, Matthias Gromeier
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Antitumor mechanisms of CD4 + T cells remain crudely defined, and means to effectively harness CD4 + T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4 + T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy. Methods The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8 + T-cell and B-cell knockout, CD4 + T-cell depletion, CD4 + T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans. Results Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4 + T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8 + T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy. Conclusion Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4 + T-cell help for antitumor CD8 + T cells, and implicates eosinophils as antitumor effectors of CD4 + T cells.
Correction: Gestational age at birth and body size from infancy through adolescence: An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies
Authors: Johan L. Vinther, Tim Cadman, Demetris Avraam, Claus T. Ekstrøm, Thorkild I. A. Sørensen, Ahmed Elhakeem, Ana C. Santos, Angela Pinot de Moira, Barbara Heude, Carmen Iñiguez, Costanza Pizzi, Elinor Simons, Ellis Voerman, Eva Corpeleijn, Faryal Zariouh, Gilian Santorelli, Hazel M. Inskip, Henrique Barros, Jennie Carson, Jennifer R. Harris, Johanna L. Nader, Justiina Ronkainen, Katrine Strandberg-Larsen, Loreto Santa-Marina, Lucinda Calas, Luise Cederkvist, Maja Popovic, Marie-Aline Charles, Marieke Welten, Martine Vrijheid, Meghan Azad, Padmaja Subbarao, Paul Burton, Puishkumar J. Mandhane, Rae-Chi Huang, Rebecca C. Wilson, Sido Haakma, Sílvia Fernández-Barrés, Stuart Turvey, Susana Santos, Suzanne C. Tough, Sylvain Sebert, Theo J. Moraes, Theodosia Salika, Vincent W. V. Jaddoe, Deborah A. Lawlor, Anne-Marie Nybo Andersen
Journal: PLoS Medicine (2023)

[This corrects the article DOI: 10.1371/journal.pmed.1004036.].
Intratumoral tertiary lymphoid structure (TLS) maturation is influenced by draining lymph nodes of lung cancer
Authors: Miao He, Qihua He, Xiuyu Cai, Jun Liu, Hongshen Deng, Feng Li, Ran Zhong, Yi Lu, Haoxin Peng, Xiangrong Wu, Zisheng Chen, Shen Lao, Caichen Li, Jianfu Li, Jianxing He, Wenhua Liang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Tertiary lymphoid structure (TLS) is an organized infiltration of immune cells, showing features of germinal center (GC) commonly seen in secondary lymphoid organs. However, its relationship with tumor-draining lymph nodes (TDLNs) has not been studied and we hypothesized that TDLN may influence maturation of intratumoral TLS in non-small cell lung cancer (NSCLC).Tissue slides of 616 patients that had undergone surgeries were examined. Cox proportional hazard regression model was used to assess risk factors of patients' survival, and logistic regression model was used for their relationship with TLS. Single-cell RNA-sequencing (scRNA-seq) was employed to explore transcriptomic features of TDLNs. Immunohistochemistry, multiplex immunofluorescence and flow cytometry were performed to analyze cellular composition. Cellular components of NSCLC samples from The Cancer Genome Atlas database were inferred with Microenvironment Cell Populations-counter (MCP-counter) method. Murine NSCLC models were used to dissect underlying mechanisms for relationship between TDLN and TLS maturation.While GC+ TLS was associated with better prognosis, GC- TLS was not. TDLN metastasis reduced the prognostic relevance of TLS, and was associated with less GC formation. Primary tumor sites showed reduced B cell infiltration in TDLN-positive patients, and scRNA-seq revealed diminished memory B cell formation in tumor-invaded TDLNs, together with an emphasis on weakened interferon (IFN)-γ response. Murine NSCLC models revealed that IFN-γ signaling is involved in memory B cell differentiation in TDLNs and GC formation in primary tumors.Our research emphasizes the influence of TDLN on intratumoral TLS maturation and suggests a role of memory B cells and IFN-γ signaling in this communication.